Process for the preparation of amides

ABSTRACT

The invention relates to a process for the preparation of fungicidally active compounds such as tricyclic amine derivatives (I). The process involves coupling of a carboxylic acid e.g. a compound of formula (II) with an aniline, e.g. a compound of formula (III) in the presence of a boronic acid catalyst or an antimony catalyst 
     
       
         
         
             
             
         
       
     
     wherein R1, R2, R3, R4, R5, R6, R7, X, Y and Het are defined in the specification.

The present invention relates to a process for the preparation of certain fungicidally active tricyclic amine derivatives and to certain fungicidally active ortho-substituted-cyclopropyl-azolcarboxamides.

Tricyclic amine derivatives having fungicidal activity are disclosed in WO/2004/035589 and WO 2007/048556. Ortho-substituted-cyclopropyl-azolcarboxamides of the formula (IA) are disclosed in WO03/074491

wherein Heta is a 5- or 6-membered heterocyclic ring containing one to three heteroatoms, each independently selected from oxygen, nitrogen and sulphur, the ring being substituted by groups R4a, R5a and R6a; R1a is hydrogen or halo; R2a is hydrogen or halo; R3a is optionally substituted C₂₋₁₂ alkyl, optionally substituted C₂₋₁₂ alkenyl, optionally substituted C₂₋₁₂ alkynyl, optionally substituted C₃₋₁₂ cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclyl; and R4a, R5a and R6a are independently selected from hydrogen, halo, cyano, nitro, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy(C₁₋₄) alkyl and C₁₋₄ haloalkoxy(C₁₋₄) alkyl, provided that at least one of R4a, R5a and R6a is not hydrogen.

The compounds disclosed in WO03/074491 have microbiocidal activity, in particular fungicidal activity.

A variety of methods for the preparation of the above compounds have been described in WO2004/035589, WO 2007/048556, and WO 2003/074491.

It has now been surprisingly found that these compounds may be advantageously obtained by coupling the respective amine and carboxylic acid in the presence of a boronic acid catalyst or an antimony catalyst.

The present invention relates to a process for the preparation of compounds of the formula (I)

wherein where Het is a 5- or 6-membered heterocyclic ring containing one to three heteroatoms, each independently selected from oxygen, nitrogen and sulphur, provided that the ring is not 1,2,3-triazole, the ring being substituted by groups R8, R9 and R10; X is a single or double bond; Y is O, S, N(R11), (CR12R13)(CR14R15)m(CR16R17)n or C═C(A)Z in which A and Z are independently C₁₋₆ alkyl or halogen; m is 0 or 1; n is 0 or 1; R1 is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, CH₂C≡CR18, CH₂CR19═CHR20, CH═C═CH₂ or COR21; R2 and R3 are each, independently, hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ haloalkoxy; R4, R5, R6 and R7 are each, independently, hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, hydroxymethyl, C₁₋₄ alkoxymethyl, C(O)CH₃ or C(O)OCH₃; R8, R9 and R10 are each, independently, hydrogen, halogen, cyano, nitro, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy(C₁₋₄)alkylene or C₁₋₄ haloalkoxy(C₁₋₄)alkylene, provided that at least one of R8, R9 and R10 is not hydrogen; R11 is hydrogen, C₁₋₄ alkyl, benzyl (in which the phenyl group is optionally substituted with up to three substituents, each independently selected from halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy), formyl, C(O)C₁₋₄ alkyl (optionally substituted by halogen or C₁₋₄ alkoxy), C(═O)O—C₁₋₆ alkyl (optionally substituted by halogen, C₁₋₄ alkoxy or cyano) or C₁₋₄ alkoxy (C₁₋₄) alkylene; R12, R13, R14, R15, R16 and R17 are each, independently, hydrogen, halogen, in hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl [both optionally substituted by halogen, hydroxy, C₁₋₄ alkoxy, ═O, aryl or O—C(O)—C₁₋₄ alkyl or a 3-7 membered carboxylic ring (itself optionally substituted by up to three methyl groups)], a 3-7 membered saturated ring (optionally substituted by up to three methyl groups and optionally containing one heteroatom selected from nitrogen and oxygen) or C₁₋₄ alkoxy; or R12 and R13 together with the carbon atom to which they are attached form the group C═O or a 3-5 membered carbocyclic ring (optionally substituted by up to three methyl groups and optionally with up to 2 heteroatoms each independently selected from O and N); or R12 and R13 together form a C₁₋₆ alkylidene (optionally substituted by up to three methyl groups) or a C₃₋₆ cycloalkylidene group (optionally substituted by up to three methyl groups); R18, R19 and R20 are each, independently, hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₁₋₄ alkoxy(C₁₋₄)alkylene; and R21 is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₄ alkoxy (C₁₋₄) alkylene, C₁₋₄ alkyl-S—(C₁₋₄) alkylene, C₁₋₄ alkoxy or aryl; comprising the step of reacting a carboxylic acid of formula (II)

wherein Het is as defined above with an aniline of the formula (III)

wherein R1, R2, R3, R4, R5, R6, R7, X and Y are as defined above; in the presence of a boronic acid catalyst or an antimony catalyst.

Halogen is fluoro, chloro, bromo or iodo; preferably fluoro, chloro or bromo.

Each alkyl moiety is a straight or branched chain and is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, neo-pentyl, n-heptyl, 1,3-dimethylbutyl, 1,3-dimethylpentyl,1-methyl-3-ethyl-butyl or 1,3,3-trimethylbutyl. Likewise, each alkylene moiety is a straight or branched chain.

Haloalkyl moieties are alkyl moieties which are substituted by one or more of the same or different halogen atoms and are, for example, CF₃, CF₂Cl, CHF₂, CH₂F, CCl₃, CF₃CH₂, CHF₂CH₂, CH₂FCH₂, CH₃CHF or CH₃CF₂.

Alkenyl and alkynyl moieties can be in the form of straight or branched chains.

Each alkenyl moiety, where appropriate, may be of either the (E)- or (Z)-configuration.

A 3-5 membered carbocyclic ring includes a spiro-three or five membered ring.

Aryl includes phenyl, naphthyl, anthracyl, fluorenyl and indanyl but is preferably phenyl.

Alkyliden moieties may be in the form of straight or branched chains. Alkyliden includes methylidene[CH₂═], ethylidene [CH₃C(H)═], n-propylidene, i-propylidene [(CH₃)₂C═], n-butylidene, i-butylidene, 2-butylidene, n-pentylidene, i-pentylidene, neo-pentylidene, 2-pentylidene, n-hexylidene, 2-hexylidene, 3-hexylidene, i-hexylidene and neo-hexylidene.

Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Cycloalkenyl includes cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

Cycloalkylidene includes cyclopropylidene [c(C₃H₄)═], cyclobutylidene, cyclopentylidene and cyclohexylidene.

In one aspect of the invention, R11 is hydrogen, C₁₋₄ alkyl, benzyl (in which the phenyl group is optionally substituted with up to three substituents, each independently selected from halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy), formyl, C(O)C₁₋₄ alkyl or C₁₋₄ alkoxy (C₁₋₄) alkylene.

In another aspect of the invention, R12, R13, R14, R15, R16 and R17 are each, independently, hydrogen, C₁₋₄ alkyl or C₁₋₄ alkoxy.

Het is preferably pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidyl, pyridazinyl, 2,3-hydro-[1, 4] oxathiine-6-yl, oxazinyl, thiazinyl or triazinyl.

Het is more preferably pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl or 2,3-dihydro-[1, 4] oxathiine-yl.

Het is even more preferably pyrrolyl, pyrazolyl, thiazolyl or pyridinyl.

Het is most preferably pyrrolyl or pyrazolyl.

Preferably X is a single bond.

In one aspect, Y is O, S, N(R11), CH₂, CH₂CH₂, CH₂CH₂CH₂, C(CH₃)₂, CH(CH₃), CH C₂H₅), C(CH₃)(C₂H₅), CH(OCH₃) or C(OCH₃)₂; more preferably N(R11), O, S, CH₂, CH₂CH₂, CH₂CH₂CH₂, C(CH₃)₂, CH(CH₃) or CH(C₂H₅); even more preferably N(R11), O, S, CH₂ or CH₂CH₂; and still more preferably O, CH₂ or N(R11). Preferably Y is O, N(R11) or (CR12R13)(CR14R15)m(CR16R17)n. More preferably Y is O or (CR12R13)(CR14R15)m(CR16R17)n. Even more preferably Y is (CR12R13)(CR14R15)m(CR16R17)n. Still more preferably Y is (CR12R13), e.g. CHCH(CH₃)CH₃.

In a further aspect, Y is C═C(A)Z in which A and Z are independently C₁₋₆ alkyl or halogen. Preferably A and Z are independently halogen, more preferably both A and Z are chlorine.

Preferably n is 0.

Preferably m is 0.

Preferably R1 is hydrogen, CH₂C≡CR18, CH═C═CH₂ or COR21.

More preferably R1 is hydrogen, CH₂C≡CH, CH═C═CH₂, C(O)H or C(O)CH₃.

Yet more preferably R1 is hydrogen, CH₂C≡CH, CH═C═CH₂ or C(O)CH₃.

Even more preferably R1 is hydrogen, CH₂C≡CH or CH═C═CH₂.

Most preferably R1 is hydrogen.

Preferably R2 is hydrogen, halogen or C₁₋₄ alkyl.

More preferably R2 is hydrogen or halogen.

Most preferably R2 is hydrogen.

Preferably R3 is hydrogen or methyl.

More preferably R3 is hydrogen.

Preferably R4 is hydrogen, C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C(O)CH₃ or C(O)OCH₃.

More preferably R4 is hydrogen, C₁₋₂ alkyl, halogen, CF₃, methoxy, C(O)CH₃ or C(O)OCH₃.

Even more preferably R4 is hydrogen, methyl, chlorine, CF₃ or methoxy.

Most preferably R4 is hydrogen or methyl.

Preferably R5 is hydrogen, C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C(O)CH₃ or C(O)OCH₃.

More preferably R5 is hydrogen, C₁₋₂ alkyl, chlorine, CF₃, methoxy, C(O)CH₃ or C(O)OCH₃.

Most preferably R5 is hydrogen or methyl.

Preferably R6 is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or C(O)CH₃.

More preferably R6 is hydrogen, methyl, methoxy or C(O)CH₃.

Most preferably R6 is hydrogen or methyl.

Preferably R7 is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or C(O)CH₃.

More preferably R7 is hydrogen, methyl, methoxy or C(O)CH₃.

Most preferably R7 is hydrogen or methyl.

Preferably R8 is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl or methoxymethylene.

More preferably R8 is hydrogen, chloro, fluoro, bromo, C₁₋₂ alkyl, CF₃, CF₂Cl, CHF₂, CH₂F or methoxymethylene.

Even more preferably R8 is hydrogen, chloro, fluoro, C₁₋₂ alkyl, CF₃, CF₂Cl, CHF₂, CH₂F or methoxymethylene.

Most preferably R8 is hydrogen, chloro, fluoro, methyl, CF₃, CHF₂ or CH₂F.

Preferably R9 is hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl or methoxymethylene.

More preferably R9 is hydrogen, chloro, fluoro, bromo, C₁₋₂ alkyl, CF₃, CF₂Cl, CHF₂, CH₂F or methoxymethylene.

Even more preferably R9 is hydrogen, chloro, fluoro, C₁₋₂ alkyl, CF₃, CF₂Cl, CHF₂, CH₂F or methoxymethylene.

Most preferably R9 is hydrogen, chloro, fluoro, methyl, CF₃, CHF₂ or CH₂F.

Preferably R10 is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl or methoxymethylene.

More preferably R10 is hydrogen, chloro, fluoro, bromo, C₁₋₂ alkyl, CF₃, CF₂Cl, CHF₂, CH₂F or methoxymethylene.

Even more preferably R10 is hydrogen, chloro, fluoro, C₁₋₂ alkyl, CF₃, CF₂Cl, CHF₂, CH₂F or methoxymethylene.

Most preferably R10 is hydrogen, chloro, fluoro, methyl, CF₃, CHF₂ or CH₂F.

In one aspect of the invention R11 is hydrogen, C₁₋₄ alkyl, benzyl, formyl, C(O)CH₃ or C(O)OC(CH₃)₃; more preferably hydrogen or C₁₋₂ alkyl.

Preferably R11 is C₁₋₄ alkyl, formyl, C(O)CH₃ or C(O)OC₁₋₆ alkyl (optionally substituted by halogen, CN or C₁₋₄ alkoxy).

More preferably R11 is C(O)OC₁₋₄ alkyl.

In one aspect of the invention R12, R13, R14, R15, R16 and R17 are each, independently, hydrogen, C₁₋₂ alkyl or methoxy.

Preferably R12 and R13 are each, independently, hydrogen, halogen, C₁₋₅ alkyl, C₁₋₃ alkoxy, CH₂OH, CH(O), C₃₋₆ cycloalkyl, CH₂O—C(═O)CH₃, CH₂—C₃₋₆ cycloalkyl or benzyl; or R12 and R13 together with the carbon atom to which they are attached form the group C═O or a 3-5 membered carbocyclic ring; or R12 and R13 together form C₁₋₅ alkylidene or C₃₋₆ cycloalkylidene.

More preferably R12 and R13 are, independently, H, CH₃, C₂H₅, n-C₃H₇, i-C₃H₇, n-C₄H₉, sec-C₄H₉, i-C₄H₉, CH(C₂H₅)₂, CH₂-cyclopropyl or cyclopentyl; or R12 and R13 together with the carbon atom to which they are attached form a 3-membered or 5-membered carbocyclic ring.

Preferably R14 is H or CH₃.

Preferably R15 is H or CH₃.

Preferably R16 is H or CH₃.

Preferably R17 is H or CH₃.

Preferably R18 is hydrogen, chloro, bromo, methyl or methoxy.

More preferably R18 is hydrogen, chloro or methyl.

Most preferably R18 is hydrogen.

Preferably R19 is hydrogen, chloro, bromo, methyl or methoxy.

More preferably R19 is hydrogen, chloro or methyl.

Most preferably R19 is hydrogen.

Preferably R20 is hydrogen, chloro, bromo, methyl or methoxy.

More preferably R20 is hydrogen, chloro or methyl.

Most preferably R20 is hydrogen.

Preferably R21 is hydrogen, methyl, OC(CH₃)₃ or CH₃OCH₂.

For example,

Het is pyrrolyl or pyrazolyl, either being substituted by groups R8, R9 and R10;

X is a single bond;

Y is (CR12R13)(CR14R15)_(m)(CR16R17)_(n) or C═C(A)Z in which A and Z are independently C₁₋₆ alkyl or halogen;

m is 0 or 1;

n is 0 or 1;

R1 is hydrogen;

R2 and R3 are each, independently, hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ haloalkoxy;

R4, R5, R6 and R7 are each, independently, hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, hydroxymethyl, C₁₋₄ alkoxymethyl, C(O)CH₃ or C(O)OCH₃;

R8, R9 and R10 are each, independently, hydrogen, halogen, cyano, nitro, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy(C₁₋₄)alkylene or C₁₋₄ haloalkoxy(C₁₋₄)alkylene, provided that at least one of R8, R9 and R10 is not hydrogen;

R12 and R13 are each, independently, hydrogen, halogen, C₁₋₅ alkyl, C₁₋₃ alkoxy, CH₂OH, CH(O), C₃₋₆ cycloalkyl, CH₂O—C(═O)CH₃, CH₂—C₃₋₆ cycloalkyl or benzyl; or R12 and R13 together with the carbon atom to which they are attached form the group C═O or a 3-5 membered carbocyclic ring;

or R12 and R13 together form C₁₋₅ alkylidene or C₃₋₆ cycloalkylidene; and

R14, R15, R16 and R17 are each, independently, H or CH₃.

Preferably, R8, R9 and R10 are each, independently, hydrogen, chloro, fluoro, methyl, CF₃, CHF₂ or CH₂F, provided that at least one of R8, R9 and R10 is not hydrogen.

Preferably, n is 0 and m is 0. Preferably, R12 and R13 are each, independently, hydrogen, C₁₋₄ alkyl or C₁₋₄ alkoxy. Preferably, R2 is hydrogen, halogen or C₁₋₄ alkyl.

Preferably, R3 is hydrogen or methyl. Preferably Het is pyrazolyl.

Preferably Het is a group of formula (VIIA)

in which R7a is selected from CF₃ and CHF₂;

Preferably, R1, R2, R3, R4, R5, R6, R7 are each independently hydrogen.

Preferably, X is a single bond;

Preferably, Y is C═CCl₂ or CHCH(CH₃)CH₃.

For example, in one embodiment:

Het is a group of formula (VIIA)

in which R7a is selected from CF₃ and CHF₂;

R1, R2, R3, R4, R5, R6, R7 are each independently hydrogen;

X is a single bond;

Y is CHCH(CH₃)CH₃; and the catalyst is a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be 3,5-bis-(trifluoromethyl)-phenylboronic acid or Sb(OEt)₃.

For example, in further embodiment:

Het is a group of formula (VIIA)

in which R7a is selected from CF₃ and CHF₂; R1, R2, R3, R4, R5, R6, R7 are each independently hydrogen; X is a single bond; Y is C═C(A)Z in which A and Z are, independently fluoro, chloro or bromo, preferably chloro; and the catalyst is a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be boric acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid.

According to a very highly preferred embodiment, the invention relates to a process for the preparation of a compound of formula (VI)

comprising reacting a carboxylic acid of formula (IV)

with an aniline of formula (V)

in the presence of a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be 3,5-bis-(trifluoromethyl)-phenylboronic acid or Sb(OEt)₃.

According to a further highly preferred embodiment of the invention, the invention relates to a process for the preparation of a compound of formula (VIII)

comprising reacting a carboxylic acid of formula (IV)

with an aniline of formula (VII)

in the presence of a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be boric acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid.

In a further embodiment, the present invention provides a process for the preparation of compounds of formula (IA)

wherein Heta is a 5- or 6-membered heterocyclic ring containing one to three heteroatoms, each independently selected from oxygen, nitrogen and sulphur, the ring being substituted by groups R4a, R5a and R6a; R1a is hydrogen or halogen; R2a is hydrogen or halogen; R3a is optionally substituted C₂₋₁₂ alkyl, optionally substituted C₂₋₁₂ alkenyl, optionally substituted C₂₋₁₂ alkynyl, optionally substituted C₃₋₁₂ cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclyl; and R4a, R5a and R6a are independently selected from hydrogen, halogen, cyano, nitro, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy(C₁₋₄) alkyl and C₁₋₄ haloalkoxy(C₁₋₄) alkyl, provided that at least one of R4a, R5a and R6a is not hydrogen comprising reacting a carboxylic acid of formula (IIA)

with an aniline of the formula (IIIA)

in the presence of a boronic acid catalyst or an antimony catalyst.

Halogen is fluoro, chloro or bromo.

Each alkyl moiety is a straight or branched chain and is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl or neo-pentyl.

When present, each optional substituent on an alkyl moiety is, independently, selected from halogen, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); where R′ and R″ are, independently, hydrogen or C₁₋₄ alkyl.

Alkenyl and alkynyl moieties can be in the form of straight or branched chains.

The alkenyl moieties, where appropriate, can be of either the (E)- or (Z)-configuration. Examples are vinyl, allyl and propargyl.

When present, each optional substituent on alkenyl or on alkynyl is, independently, selected from those optional substituents given above for an alkyl moiety.

Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

When present, each optional substituent on cycloalkyl is, independently, selected from C₁₋₃ alkyl and those optional substituents given above for an alkyl moiety.

The term heterocyclyl refers to a non-aromatic or aromatic ring containing up to 10 atoms including one or more (preferably one or two) heteroatoms selected, each independently, from O, S and N. Examples of such rings include 1,3-dioxolanyl, tetrahydrofuranyl, morpholinyl, thienyl and furyl.

When present, each optional substituent on phenyl or on heterocyclyl is, independently, selected from C₁₋₆ alkyl and those optional substituents given above for an alkyl moiety. When present, there are up to four optional substituents on phenyl, each independently selected.

When present, each optional substituent on an alkyl moiety is, independently, selected from the preferred list of halo, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, cyano and nitro.

When present, each optional substituent on alkenyl or on alkynyl is, independently, selected from the preferred list of halogen and cyano.

When present, each optional substituent on cycloalkyl is, independently, selected from the preferred list of methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy and cyano.

When present, each optional substituent on phenyl or on a heterocyclyl group is, independently, selected from the preferred list of halo, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy and cyano.

It is preferred that Heta is pyrrolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, thiophenyl, furyl, isothiazolyl or isoxazolyl (more preferably pyrrolyl, pyrazolyl or thiazolyl), each being substituted by groups R4a, R5a and R6a.

Preferably

Heta is pyrrolyl, pyrazolyl or thiazolyl, each being substituted by groups R4a, R5a, R6a; R1a is hydrogen, fluoro, chloro or bromo; R2a is hydrogen, fluoro, chloro or bromo; R3a is optionally substituted C₂₋₁₂ alkyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted C₂₋₁₂ alkenyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄-alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted C₂₋₁₂ alkynyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted C₃₋₁₂ cycloalkyl, wherein, when present, each optional substituent is, independently, selected from C₁₋₃ alkyl, fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted phenyl, wherein, when present, each optional substituent is, independently, selected from C₁₋₆ alkyl, fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); or optionally substituted heterocyclyl, wherein, when present, each optional substituent is, independently, selected from C₁₋₆ alkyl, fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N; R′ and R″ are, independently, hydrogen or C₁₋₄ alkyl; and R4a, R5a, and R6a are, independently, selected from hydrogen, fluoro, chloro, bromo, cyano, nitro, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl and C₁₋₄ haloalkoxy(C₁₋₄)alkyl, provided that at least one of R4a, R5a, and R6a is not hydrogen.

Preferably R1a and R2a are, independently, hydrogen or fluoro.

Preferably R3a is C₂₋₆ alkyl, optionally substituted C₃₋₈ cycloalkyl, phenyl, thienyl or furyl.

Preferably R4a, R5a and R6a are, independently, selected from hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy(C₁₋₄)alkyl; provided that at least one of R4a, R5a and R6a is not hydrogen. More preferably R4a, R5a, and R6a are, independently, selected from hydrogen, halogen, methyl, C₁₋₂ haloalkyl and methoxymethyl; provided that at least one of R4a, R5a and R6a is not hydrogen.

Preferably, Heta is pyrazolyl. More preferably, Heta is pyrazol-4-yl. More preferably, Heta is a group of formula (VIIA)

wherein R7a is selected from CF₃ and CHF₂. Preferably, R7a is CHF₂.

Preferably, R1a is hydrogen. Preferably, R2a is hydrogen. More preferably, R1a and R2a are hydrogen.

Preferably, R3a is optionally substituted cycloalkyl. More preferably, R3a is optionally substituted cyclopropyl. More preferably, R3a is a group of the formula (VIIIA)

wherein R8a is H or C₁₋₆ alkyl. Preferably, R8a is H or Methyl. More preferably, R8a is H.

For example,

Heta is a group of formula (VIIA)

wherein R7a is selected from CF₃ and CHF₂; R1a is R2a, and R3a are hydrogen; R3a is a group of the formula (VIIIA)

wherein R8a is H or C1-4 alkyl, preferably H or Methyl, more preferably H; and the catalyst is a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be boric acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid.

According to a very highly preferred embodiment, the invention relates to a process for the preparation of a compound of formula (IXA)

comprising reacting an acid of formula (XA)

with an aniline of formula (XIA)

in the presence of a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be boric acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid.

Ratio of Reagents

Preferably, the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 10:1 to 1:10. More preferably, the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 5:1 to 1:5. More preferably, the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 2:1 to 1:2. More preferably, the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 1.2:1 to 1:1.2. More preferably, the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 1.1:1 to 1:1.1.

Solvent

The reaction of the invention is optionally (and preferably) conducted in a suitable solvent. Suitable solvents include, but are not limited to, linear, branched or cyclic aliphatic hydrocarbons, such as ligroin or cyclohexane, pentane, hexane, heptane, octane, as well as aromatic solvents, such as benzene, toluene, xylene, monochlorobenzene, dichlorobenzene, trichlorobenzene.

A preferred solvent is xylene.

Temperature

The reaction of the invention may be carried out at a temperature such that an acceptable rate of reaction is attained. Preferably, the reaction is conducted at a temperature of from 0° C. to 200° C. More preferably, the reaction is conducted at a temperature of from 50° C. to 180° C. More preferably, the reaction is conducted at a temperature of from 100° C. to 170° C. More preferably, the reaction is conducted at a temperature of from 130° C. to 150° C.

Removal of Water

Preferably, provision is made for removal of water from the reaction mixture, e.g. removal of water prior to completion of the reaction. Water may be removed from the reaction continuously. A suitable method is azeotropic removal of water. Suitable apparatus for conducting azeotropic removal of water will be known to those skilled in the art. We have found that removal of water is highly desirable in order to achieve a commercially useful conversion to product.

Boronic Acid

Examples of the boronic acids include boric acid, phenylboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-methylphenylboronic acid, 2,3-dimethylphenylboronic acid, 4-dimethylphenylboronic acid, 2,5-dimethylphenylboronic acid, 2-ethylphenylboronic acid, 4-n-propylphenylboronic acid, 4-isopropylphenylboronic acid, 4-n-butylphenylboronic acid, 4-tert-butylphenylboronic acid, 1-naphthylboronic acid, 2-naphthylboronic acid, 2-biphenylboronic acid, 3-biphenylboronic acid, 4-biphenylboronic acid, 2-fluoro-4-biphenylboronic acid, 2-fluorenylboronic acid, 9-fluorenylboronic acid, 9-phenanthrenylboronic acid, 9-anthracenylboronic acid, 1-pyrenylboronic acid, 2-trifluoromethylphenylboronic acid, 3-trifluoromethylphenylboronic acid, 4-trifluorophenylboronic acid, 3,5-bis(trifluoromethyl)phenylboronic acid, 2-methoxyphenylboronic acid, 3-methoxyphenylboronic acid, 4-methoxyphenylboronic acid, 2,5-dimethoxyphenylboronic acid, 4,5-dimethoxyphenylboronic acid, 2,4-dimethoxyphenylboronic acid, 2-ethoxyphenylboronic acid, 3-ethoxyphenylboronic acid, 4-ethoxyphenylboronic acid, 4-phenoxyboronic acid, 4-methylenedioxyphenylboronic acid, 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4-fluorophenylboronic acid, 2,4-difluorophenylboronic acid, 2,5-difluorophenylboronic acid, 4,5-difluorophenylboronic acid, 3,5-difluorophenylboronic acid, 2-formylphenylboronic acid, 3-formylphenylboronic acid, 4-formylphenylboronic acid, 3-formyl-4-methoxyphenylboronic acid, 2-cyanophenylboronic acid, 3-cyanophenylboronic acid, 4-cyanophenylboronic acid, 3-nitrophenylboronic acid, 3-acetylphenylboronic acid, 4-acetylphenylboronic acid, 3-trifluoroacetylphenylboronic acid, 4-trifluoroacetylphenylboronic acid, 4-methylthiophenylboronic acid, 4-vinylphenylboronic acid, 3-carboxyphenylboronic acid, 4-carboxyphenylboronic acid, 3-aminophenylboronic acid, 2-(N,N-dimethylamino)phenylboronic acid, 3-(N,N-dimethylamino)phenylboronic acid, 4-(N,N-dimethylamino)phenylboronic acid, 2-(N,N-diethylamino)phenylboronic acid, 3-(N,N-diethylamino)phenylboronic acid, 4-(N,N-diethylamino)phenylboronic acid, 2-(N,N-dimethylaminomethyl)phenylboronic acid, furan-2-boronic acid, furan-3-boronic acid, 4-formyl-2-furanboronic acid, dibenzofuran-4-boronic acid, benzofuran-2-boronic acid, thiophene-2-boronic acid, thiophene-3-boronic acid, 5-methylthiophene-2-boronic acid, 5-chlorothiophene-2-boronic acid, 4-methylthiophene-2-boronic acid, 5-methylthiophene-2-boronic acid, 2-acetylthiophene-5-boronic acid, 5-methylthiophene-2-boronic acid, benzothiophene-2-boronic acid, dibenzothiophene-4-boronic acid, pyridine-3-boronic acid, pyridine-4-boronic acid, pyrimidine-5-boronic acid, quinoline-8-boronic acid, isoquinoline-4-boronic acid, 4-benzenebis(boronic acid), phenylboronic acid-pinacol ester, and 4-cyanophenylboronic acid-pinacol ester.

A preferred class of boronic acids are aryl boronic acids. Most preferred is 2-(N,N-dimethylaminomethyl)phenylboronic acid and 3,5-trifluoromethylphenylboronic acid.

An alternative preferred boronic acid is boric acid.

Antimony

Antimony for use as a catalyst in the present invention may be, for example, antimony III or antimony V.

Examples of antimony for use as a catalyst include antimony complexes, e.g. organo antimony complexes such as aryl antimony complexes and saturated and unsaturated carbon chain antimony complexes, with the ligand complexed to the antimony with a suitable coordination atom, e.g. selected from O, S or N. Example of suitable antimony catalysts include:

antimony halides, e.g. SbCl₃, antimony oxides, e.g. Sb₂C₃, antimony alkoxides, e.g. Sb(ORx)₃ in which Rx is alkyl, alkenyl, alkynyl, e.g. C₁-C₄ alkyl, C₂-C₄ alkenyl, e.g. C₃-C₄ alkynyl, in particular Sb(OEt)₃, antimony carboxylic acids, e.g. Sb(C₂CRx)₃ in which Rx is as defined above, in particular Sb(Ac)₃.

Examples of antimony V catalysts include aryl antimony complexes, such as those mentioned in Nomura et al., Chemistry Letters, The Chemical Society of Japan, 1986, pages 1901-1904. These include antimony complexed with aryl groups and carboxylates, e.g. Ph₃Sb(C₂CRx)₂ in which Rx is as defined above, particularly Ph₃Sb(OAc)₂, and antimony oxides complexed with aryl groups, e.g. Ph₃SbO.

Catalyst Recycle

Preferably the catalyst is recycled, e.g. by extracting the catalyst from the reaction solution into the aqueous phase. Extraction of the catalyst may be achieved by changing the pH of the reaction solution, e.g. to alkaline pH, so that the catalyst transfers from the organic phase to the aqueous phase. The catalyst may subsequently be transferred from the aqueous phase to fresh reactant solution by changing the pH, e.g. to acidic pH.

Boronic acid catalysts, such as 3,5-bis-(trifluoromethyl)-phenylboronic acid, are particularly suitable for catalyst recycle by extracting the catalyst from the reactant solution to aqueous phase.

Amount of Catalyst

Preferably, the amount of catalyst employed is up to 50 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is up to 25 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is up to 15 mol % based on the amount of carboxylic acid (II) or (IIA).

Preferably, the amount of catalyst employed is at least 0.01 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is at least 0.1 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is at least 1 mol % based on the amount of carboxylic acid (II) or (IIA).

Preferably, the amount of catalyst employed is between 0.01 and 50 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is between 0.1 and 25 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is between 1 and 15 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is between 8 and 12 mol % based on the amount of carboxylic acid (II) or (IIA).

Preferably, the amount of catalyst employed is up to 50 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is up to 25 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is up to 15 mol % based on the amount of aniline (III) or (IIIA).

Preferably, the amount of catalyst employed is at least 0.01 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is at least 0.1 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is at least 1 mol % based on the amount of aniline (III) or (IIIA).

Preferably, the amount of catalyst employed is between 0.01 and 50 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is between 0.1 and 25 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is between 1 and 15 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is between 8 and 12 mol % based on the amount of aniline (III) or (IIIA).

Usually one type of catalyst will be used in a reaction. However, the invention also covers reactions in which more than one type of catalyst is used, e.g. either separately, sequentially or simultaneously. For example, more than one type of boronic catalyst or antimony catalyst may be used or a boronic acid catalyst and an antimony catalyst may be used.

Synthesis of Starting Materials

Suitable methods for the preparation of carboxylic acids (II) and anilines (III) are disclosed in WO04/035589 and WO 2007/048556. Suitable methods for the preparation of carboxylic acids (IIA) and anilines (IIIA) are disclosed in WO03/074491. Other methods will be apparent to those skilled in the art.

Workup and Isolation of Products

Workup of the reaction mixture is achieved according to well known procedures of synthetic organic chemistry. For example, an aqueous workup may be achieved by the addition of water (or other aqueous solution), and extraction of the desired product with a suitable organic solvent.

Alternatively, the product may be isolated by removing any solvent present by distillation, e.g. under reduced pressure.

Purification of the product may be achieved by any one of a number of methods, e.g. distillation, recrystallization and chromatography.

The present invention will now be described by way of the following non-limiting examples. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

All references mentioned herein are incorporated by reference in their entirety. All aspects and preferred features of the invention may be combined with each other, except where this is evidently not possible.

FIG. 1

FIG. 1 shows the reaction profile of the boronic acid catalysed reaction of Example 2:

using 10 mole % catalyst, under azeotropic reflux in toluene. The X axis indicates time in hours and the Y axis indicates mole fraction. Triangles represent the acid reactant, diamonds represent the aniline reactant, circles represent product.

FIG. 2

FIG. 2 shows a profile of mole fraction of 3,5-bis-(trifluoromethyl)-phenylboronic acid catalyst in the organic phase (toluene) versus pH. Circles represent modelled data, diamonds represent experimental data.

EXAMPLES Example 1 Reaction Sequence (Absence of Catalyst)

An oven-dried round bottomed flask was evacuated and refilled with nitrogen three times. The flask was fitted with a dropping funnel containing charged 3 Å molecular sieves, and this was connected to the nitrogen line. 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (0.36 g, 2 mmol), 9-Isopropyl-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (0.4 g, 2 mmol) were added to the flask, followed by anhydrous toluene (2 mL) via syringe. The mixture was azeotropically refluxed overnight, under nitrogen. After this time, the solution was cooled and concentrated in vacuo to give a pale brown solid. ¹H and ¹⁹F NMR and GC analyses showed only 5% conversion to amide product.

Example 2 Reaction Sequence

An oven-dried flask was evacuated and refilled with nitrogen three times. The flask was fitted with a dropping funnel containing charged 3 Å molecular sieves. 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (0.36 g, 2 mmol), 9-Isopropyl-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (0.4 g, 2 mmol) were added to the flask, followed by 3,5-bis-(trifluoromethyl)-phenylboronic acid (26 mg, 5 mol %) and anhydrous toluene (4 mL). The mixture was heated to reflux and was azeotropically refluxed overnight under nitrogen. A sample was analysed by GC which indicated quantitative conversion to the amide and so the solution was cooled, and quenched with saturated aqueous solutions of sodium hydrogencarbonate (10 mL) and ammonium chloride (10 mL).

The aqueous layer was extracted with ethyl acetate (3×10 mL). Combined organic extracts were washed with water (10 mL), dried with MgSC₄ and concentrated in vacuo to give a brown solid which was identified as the amide product by ¹H and ¹⁹F NMR, and GC-MS (0.55 g, 76%).

The boronic acid catalysed reaction was profiled using 10 mole % catalyst, under azeotropic reflux in toluene. The removal of water by azeotropic reflux appears to be advantageous, since without these conditions, reactions were not complete after 18 hours. See FIG. 1.

Recycling of the catalyst was by extracting the boronic acid from the reaction mass with strong aqueous alkali, acidifying and then re-extracting into toluene ready for the next batch was investigated. The phase partition was modelled using the calculated Log P (3.013) and pK_(a) (6.57) and the experimental values are close although show a slight tail at the higher pH possibly due to the high ionic strength. See FIG. 2.

Catalyst recycle would significantly reduce the cost contribution of catalyst to the product.

Example 3 Reaction Sequence

An oven-dried flask was evacuated and refilled with nitrogen three times. The flask was fitted with a dropping funnel containing charged 3 Å molecular sieves. 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (0.36 g, 2 mmol), 9-Isopropyl-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (0.4 g, 2 mmol) were added to the flask, followed by antimony (III) ethoxide (34 μL, 5 mol %) and anhydrous toluene (4 mL). The reaction was refluxed azeotropically overnight, under an atmosphere of nitrogen. A sample was analysed by GC which indicated quantitative conversion to the amide and so the solution was quenched with methanol (5 mL), and a solid crashed out of the resulting solution. This suspension was filtered through a pad of Celite, washing with 50/50 ethyl acetate/acetone (10 mL). The resulting solution was concentrated in vacuo to yield a yellow solid which was identified by ¹H and ¹⁹F NMR, and GCMS analyses as the amide product (0.53 g, 73%).

Example 4 Reaction Sequence

Actual Strength 100% Mol Mol. Materials Wt (g) (%) Wt. (g) Wt. mmol. Ratio DF-Pyrazole 0.41 95.9 0.393 176 2.2 1.0 acid (IV) Aniline (VII) 0.52 95 0.494 239 2.2 1.0 Boric acid 0.0142 98 0.0139 61.8 0.23 0.1 Xylene 15 ml 99 — — — —

A 50 ml three neck round bottom flask was fitted with a magnetic flea, thermometer, oil bath, condenser, and Dean & Stark apparatus filled with 3A molecular sieves 8-12 mesh (with 10 ml xylene). The system was purged with nitrogen and vented to atmosphere.

DF-Pyrazole acid (compound IV) (0.41 g), aniline (compound VII) (0.56 g), xylene (15 ml) and boric acid catalyst (14.2 mg) were charged to the flask. The mixture was heated to reflux (˜144 deg C.) and held on temperature for 8 hrs. Reaction was monitored via GCMS.

$\begin{matrix} {{Conversion} = {94\% \mspace{14mu} {conversion}\mspace{14mu} {based}\mspace{14mu} {on}\mspace{14mu} {compound}\mspace{14mu} ({IV})\mspace{14mu} {by}\mspace{14mu} {GCMS}}} \\ {= {54\% \mspace{14mu} {conversion}\mspace{14mu} {based}\mspace{14mu} {on}\mspace{14mu} {compound}\mspace{14mu} ({VII})\mspace{14mu} {by}\mspace{14mu} {GCMS}}} \\ {= {55\% \mspace{14mu} {conversion}\mspace{14mu} {by}\mspace{14mu} {NMR}}} \end{matrix}$

GC/MS Details: The product had the same retention time, molecular ion (M⁺331) and fragmentation pattern as found with the authentic compound.

NMR: NMR spectrum of product was consistent with that for authentic material.

Example 5 Reaction Sequence

A selection of catalysts (10 mol %) were screened. The procedure in Example 4 was repeated varying the catalyst employed.

Catalyst Solvent Connditions Results None Xylene Vigorous reflux 2% conversion to with Dean & desired product Stark set-up Relatively clean 5 hr reaction B(OH)₃ Xylene Vigorous reflux 55% conversion with Dean & to desired product Stark set-up Relatively clean 8 hr reaction

Xylene Vigorous reflux with Dean & Stark set-up. 8 hr 55% conversion to the desired product

Conversions were determined by GCMS analysis. The results presented in the table are based on consumption of the aniline component. Conversions based on carboxylic acid consumption are different, presumably due to response factor differences. NMR analysis has shown that monitoring aniline consumption gives the best measure of reaction conversion.

Desired product was formed in all cases, but reaction rate was very slow without catalyst present. Reasonably good rates were achieved with both of the boron-based catalysts tried. Interestingly, a synthetically advantageous rate was achieved with cheap boric acid catalyst (55% conversion in 8 hr), The product was isolated and its structure confirmed by NMR analysis.

Example 6 Reaction Sequence

Mo- Actual Strength 100% lecular Molar Materials Weight % Weight weight Mmol Ratio DF-Pyrazole 0.5 93.0 0.465 176 2.6 1.0 acid (X) BiCP Aniline 0.94 48.7 0.458 173 2.6 1.0 (XI) 2-(N,N- 0.047 98 0.046 179 0.26 0.1 dimethyl- aminomethyl) phenylboronic acid Xylene 20 ml 99 17.2 106 162 62.4

A 50 ml three neck round bottom flask was fitted with a magnetic flea, thermometer, oil bath, condenser, and Dean & Stark apparatus filled with 3 Å molecular sieves 8-12 mesh (with 10 ml xylene). The system was purged with nitrogen and vented to the atmosphere.

DF-pyrazole acid X (0.5 g), BiCP-aniline XI (0.94 g), xylene (20 ml) and 2-(N,N-dimethyl aminomethyl)phenylboronic acid catalyst (47 mg) were charged to the flask. The mixture was heated to reflux (˜143° C.) and held at this temperature for 10 hours.

The reaction was monitored via HPLC; 45% conversion being achieved after 5 hours, and 58% after 10 hours.

Product identity was confirmed by HPLC and GCMS comparison with authentic material.

Example 7 Reaction Sequence

The procedure of Example 6 was repeated varying the catalyst employed.

Solvent Conditions Time Catalyst Conversion Xylene Reflux, Dean 5 hours None <1% and Stark Xylene Reflux, Dean 5 hours 2-(N,N- 45% and Stark dimethylaminomethyl) phenylboronic acid (10 Mol %) Xylene Reflux, Dean 5 hours Boric Acid 25% and Stark (10 Mol %) Xylene Reflux, Dean 20 hours  Boric Acid 50% and Stark (10 Mol %)

These results show that in the absence of catalysts, virtually no reaction occurred after 5 hours at 140° C.

Addition of catalyst, however, had a dramatic effect on reaction rate—45% conversion being achieved after 5 hours with 10% of 2-(N,N-dimethylaminomethyl) phenylboronic acid. Boric acid catalyst was less effective, but still generated a useful reaction rate (25% conversion after 5 hours). Product identity was confirmed by GCMS comparison with authentic material. 

1-16. (canceled)
 17. A process for (a) the preparation of compounds of the formula (I)

wherein Het is pyrrolyl or pyrazolyl, either being substituted by groups R8, R9 and R10; X is a single bond; Y is (CR12R13)(CR14R15)m(CR16R17)n or C═C(A)Z in which A and Z are independently C₁₋₆ alkyl or halogen; m is 0 or 1; n is 0 or 1; R1 is hydrogen; R2 and R3 are each, independently, hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ haloalkoxy; R4, R5, R6 and R7 are each, independently, hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, hydroxymethyl, C₁₋₄ alkoxymethyl, C(O)CH₃ or C(O)OCH₃; R8, R9 and R10 are each, independently, hydrogen, halogen, cyano, nitro, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy(C₁₋₄)alkylene or C₁₋₄ haloalkoxy(C₁₋₄)alkylene, provided that at least one of R8, R9 and R10 is not hydrogen; R12 and R13 are each, independently, hydrogen, halogen, C₁₋₅ alkyl, C₁₋₃ alkoxy, CH₂OH, CH(O), C₃₋₆ cycloalkyl, CH₂O—C(═O)CH₃, CH₂—C₃₋₆ cycloalkyl or benzyl; or R12 and R13 together with the carbon atom to which they are attached form the group C═O or a 3-5 membered carbocyclic ring; or R12 and R13 together form C₁₋₅ alkylidene or C₃₋₆ cycloalkylidene; and R14, R15, R16 and R17 are each, independently, H or CH₃; comprising the step of reacting a carboxylic acid of formula (II)

wherein Het is as defined above with an aniline of the formula (III)

wherein R1, R2, R3, R4, R5, R6, R7, X and Y are as defined above; in the presence of a boronic acid catalyst or an antimony catalyst; or (b) the preparation of compounds of the formula (IA)

wherein Heta is pyrrolyl, pyrazolyl or thiazolyl, each being substituted by groups R4a, R5a, R6a; R1a is hydrogen, fluoro, chloro or bromo; R2a is hydrogen, fluoro, chloro or bromo; R3a is optionally substituted C₂₋₁₂ alkyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted C₂₋₁₂ alkenyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄-alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted C₂₋₁₂ alkynyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted C₃₋₁₂ cycloalkyl, wherein, when present, each optional substituent is, independently, selected from C₁₋₃ alkyl, fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted phenyl, wherein, when present, each optional substituent is, independently, selected from C₁₋₆ alkyl, fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N and R′R″NN═C(H); or optionally substituted heterocyclyl, wherein, when present, each optional substituent is, independently, selected from C₁₋₆ alkyl, fluoro, chloro, bromo, hydroxy, cyano, C₁₋₄ alkoxyC(═O), formyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkylthio, HC(OR′)═N; R′ and R″ are, independently, hydrogen or C₁₋₄ alkyl; and R4a, R5a, and R6a are, independently, selected from hydrogen, fluoro, chloro, bromo, cyano, nitro, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl and C₁₋₄ haloalkoxy(C₁₋₄)alkyl, provided that at least one of R4a, R5a, and R6a is not hydrogen. comprising reacting a carboxylic acid of formula (IIA)

with an aniline of the formula (IIIA)

in the presence of a boronic acid catalyst or an antimony catalyst.
 18. The process according to claim 1 wherein the boronic acid catalyst is an aryl boronic acid.
 19. The process according to claim 1 wherein the boronic acid catalyst is 2-(N,N-dimethylaminomethyl)phenylboronic acid, boric acid or 3,5-trifluoromethylphenyl boronic acid.
 20. The process according to claim 1 wherein the antimony catalyst is Sb(OEt)₃.
 21. The process according to claim 1 wherein the catalyst is employed in an amount of between 1 and 15 mol % based on the amount of carboxylic acid (II) or (IIA).
 22. The process according to claim 1 wherein the catalyst is employed in an amount of between 1 and 15 mol % based on the amount of aniline (III) or (IIIA).
 23. The process according to claim 1 wherein the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 2:1 to 1:2.
 24. The process according to claim 1 wherein Het is a group of formula (VIIA)

in which R7a is selected from CF₃ and CHF₂; and/or wherein Y is CHCH(CH₃)CH₃ or C═CCl₂; and/or wherein R2, R3, R4, R5, R6, R7 are independently selected from hydrogen.
 25. The process according to claim 1 wherein Y is CHCH(CH₃)CH₃.
 26. The process according to claim 1 wherein Y is C═CCl₂.
 27. A process according to claim 1 for the preparation of a compound of formula (VI)

comprising reacting a carboxylic acid of formula (IV)

with an aniline of formula (V)

in the presence of a boronic acid catalyst or an antimony catalyst.
 28. A process according to claim 1 for the preparation of a compound of formula (VIII)

comprising reacting a carboxylic acid of formula (IV)

with an aniline of formula (VII)

in the presence of a boronic acid catalyst or an antimony catalyst.
 29. The process according to claim 1, wherein Heta is a group of formula (VIIA)

in which R7a is selected from CF₃ and CHF₂; and/or wherein R3a is a group of the formula (VIIIA)

in which R8 is H or C1-6 alkyl.
 30. A process according to claim 1 for the preparation of a compound of formula (IXA)

comprising reacting a carboxylic acid of formula (IV)

with an aniline of formula (XIA)

in the presence of a boronic acid catalyst or an antimony catalyst. 